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Methylophiopogonanone A (MOA) is an abundant homoisoflavonoid in the Chinese herb Ophiopogonis Radix. Recent investigations revealed that MOA inhibited several human cytochrome P450 enzymes (CYPs) and stimulated OATP1B1. However, the inhibitory effects of MOA on phase II drug‐metabolizing enzymes, such as human UDP‐glucuronosyltransferases (hUGTs), have not been well investigated. Herein, the inhibition potentials of MOA on hUGTs were assessed. The results clearly demonstrated that MOA dose‐dependently inhibited all tested hUGTs including UGT1A1 (IC50 = 1.23 μM), one of the most important detoxification enzymes in humans. Further investigations showed that MOA strongly inhibited UGT1A1‐catalysed NHPH‐O‐glucuronidation in a range of biological settings including hUGT1A1, human liver microsomes (HLM) and HeLa cells overexpressing UGT1A1. Inhibition kinetic analyses demonstrated that MOA competitively inhibited UGT1A1‐catalysed NHPH‐O‐glucuronidation in both hUGT1A1 and HLM, with Ki values of 0.52 and 1.22 μM, respectively. Collectively, our findings expanded knowledge of the interactions between MOA and human drug‐metabolizing enzymes, which would be very helpful for guiding the use of MOA‐related herbal products in clinical settings. [ABSTRACT FROM AUTHOR]

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment. Image 1 • Qingfei Paidu decoction (QPD) dose-dependently inhibits CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 in a reversible manner. • QPD inhibits CYP3A in a time- and NADPH-dependent manner in liver microsomes from both humans and rats. • QPD significantly increases the plasma exposure and half-life of lopinavir in rats. • Fructus Aurantii Immaturus (Zhishi) in QPD plays a crucial role in CYP3A inactivation. [ABSTRACT FROM AUTHOR]